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Curr Otorhinolaryngol Rep. Author manuscript; available in PMC 2014 March 01.

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Curr Otorhinolaryngol Rep. 2013 March 1; 1(1): 5160. doi:10.1007/s40136-012-0003-4.

Topical Drug Delivery for Chronic Rhinosinusitis


Jonathan Liang, MD and Andrew P. Lane, MD
Department of Otolaryngology Head and Neck Surgery, Johns Hopkins University School of
Medicine

Abstract

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Chronic rhinosinusitis is a multifactorial disorder that may be heterogeneous in presentation and


clinical course. While the introduction of endoscopic sinus surgery revolutionized surgical
management and has led to significantly improved patient outcomes, medical therapy remains the
foundation of long-term care of chronic rhinosinusitis, particularly in surgically recalcitrant cases.
A variety of devices and pharmaceutical agents have been developed to apply topical medical
therapy to the sinuses, taking advantage of the access provided by endoscopic surgery. The goal of
topical therapy is to address the inflammation, infection, and mucociliary dysfunction that
underlies the disease. Major factors that impact success include the patients sinus anatomy and
the dynamics of the delivery device. Despite a growing number of topical treatment options, the
evidence-based literature to support their use is limited. In this article, we comprehensively review
current delivery methods and the available topical agents. We also discuss biotechnological
advances that promise enhanced delivery in the future, and evolving pharmacotherapeutical
compounds that may be added to rhinologists armamentarium. A complete understand of topical
drug delivery is increasingly essential to the management of chronic rhinosinusitis when
traditional forms of medical therapy and surgery have failed.

Keywords
topical; drug delivery; chronic rhinosinusitis; saline; antimicrobials; corticosteroids

Introduction
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Since its introduction over three decades ago1, endoscopic sinus surgery (ESS) has become
the standard of care for the treatment of medically recalcitrant chronic rhinosinusitis (CRS).
The primary goal of functional endoscopic sinus surgery is to improve patient symptoms by
restoring ostial patency and mucociliary function. As experience with endoscopic sinus
surgery has grown, it has become apparent that these aims are achieved most successfully
when inflammatory sinus disease stems principally from anatomic obstruction. In some
forms of CRS, however, there appears to be an intrinsic mucosal inflammatory component
that is not directly amenable to surgical correction. In these cases, the goals of the
endoscopic procedure shift from reversing the disease process to providing access for longterm sinonasal endoscopic surveillance and the application of topical therapies. Locallydelivered pharmacotherapy has increasingly been viewed as a new frontier in CRS
management, and the armamentarium of topical options has greatly expanded over the past

Corresponding author: Andrew P. Lane, MD, Department of Otolaryngology Head and Neck Surgery, Johns Hopkins University
School of Medicine, 601 N. Caroline St., 6th Floor, Baltimore, MD 21287, Phone: 410-955-7808, Fax: 410-614-8610,
alane3@jhmi.edu.
Disclosure
No potential conflicts of interest relevant to this article were reported.

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decade. To understand the current and future status of topical therapies for CRS, knowledge
of the methods of delivery as well as the available drugs and compounds is needed. The
scientific evidence supporting topical therapy for CRS remains most robust for long-utilized
agents such as saline and intranasal corticosteroid sprays. While newer topical preparations
such as antimicrobials, surfactant agents, and organic natural products are continuing to
advance the ability of physicians to manage inflammatory sinus disease, the choice of
specific agents and the optimal mechanisms of delivery remain subjects of active
investigation and debate.
Three mechanisms have been proposed to centrally contribute to CRS pathophysiology:
mucosal inflammation, local infection, and mucociliary dysfunction23. Topical medical
therapy has been designed to target each of these, and its success relies upon both
mechanical irrigation and pharmaceutical delivery45. Irrigation helps to removal pollutants,
antigens, inflammatory byproducts, mucus, and bacteria from the sinonasal tract. Factors
that optimize the mechanical action of topical therapy often do so at the expense of optimal
drug delivery, for which prolonged mucosal contact time and minimal depletion are
desirable5. These competing goals present challenges in developing medications and
delivery systems for the treatment of CRS.

Methods of Delivery
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Sinonasal drug delivery fluid dynamics is a rapidly growing area of intense research
investigation. This high level of interest is directly tied to a number of commercial products,
each with variable published experimental support. Studies on delivery methods have
focused on the state of the paranasal sinuses (non-operated vs. post-surgical) and the device
dynamics (device, techniques, volume, position).
Sinus surgery is a pre-requisite for effective sinus topical drug delivery
It is well established that the delivery of topical solution to the non-operated sinuses is very
limited6. Pressurized nasal spray provide only nasal cavity penetration at best, and squeeze
bottle and Neti pot irrigation only provided some maxillary sinus and ethmoid sinus
penetration6. The frontal and sphenoid sinuses are essentially not accessible prior to
surgery6. Olson evaluated three methods of nasal irrigation in healthy non-operated
individuals found distribution in the nasal cavity, but poor distribution in the sinuses with all
techniques7. With CRS, mucosal inflammation and edema further limit the penetration of
nasal irrigation or sprays8. Grobler et al. showed that an ostial size of greater than 3.95 mm
is required to see penetration into the maxillary sinus9.

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Endoscopic sinus surgery allows for more effective delivery of topical drugs, although the
degree to which access is increased depends on the extent and technique of surgery. With
the advent of balloon dilation technology, an even wider variability in the size of postsurgical sinus openings exists. This heterogeneity creates a confounding variable in
determining the effectiveness of topical drug delivery in post-surgical sinus cavities. In
Harveys cadaveric study, delivery to the sinuses improved after sinus surgery regardless of
the delivery device6. Studies have shown that irrigation with douching or bulb irrigation is
more effective than sprays, nebulizers, or atomizers in reaching post-operative sinus
cavities1011.
Devices to deliver saline
There are a number of devices on the market for topical saline delivery into the nose and
paranasal sinuses. They vary mainly in the volume and pressure of delivery (Table 1).
Regardless of device or technique, penetration into the sinuses is very limited in nonoperated sinuses6, 89. Two common high-volume techniques for delivery of nasal saline are
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the squeeze bottle (high pressure) and the Neti pot (low pressure). Large volume systems
have been shown to have the best efficacy in post-ESS cavities, with large volume high
pressure devices being superior6, 912. Low volume devices, such as pump spray (high
pressure) or nebulizer (low pressure), poorly penetrate the sinuses even after ESS6, 12. Less
than 50% of most low volume devices reach the middle meatus13. Low volume systems
should be considered a nasal cavity treatment because both pre- and post-surgical
penetration into the sinuses is extremely poor.
Drug delivery devices
Nasal pump sprays are a popular option for topical drug delivery because of their ease of
use, and many different formulations are available in this format. The main factors
associated with particle penetration include the size of the sinus ostia, the size of the particle,
and the flow rate of the aerosol1415. Particles >10 m in size usually do not make it past the
nasal cavity, and particles <5 m are needed to enter into the lungs. Hyo et al. theorized that
ideal particle size for maxillary sinus penetration is between 3 to 10 m, and further work by
Saijo et al. demonstrated that smaller particle size (5.63 m vs. 16.37 m), 45 insertion angle
(vs. 30 insertional angle), and higher flow rate improved maxillary sinus penetration14, 16.

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Typical nasal pump sprays generate droplets of 50 to 100 m in diameter size, and deliver
70 to 150 L of drug per puff, at standard velocities of 7.5 to 20 L/min5. A large fraction of
the spray is deposited in the anterior nasal cavity without any significant penetration into the
paranasal sinuses1718. Furthermore, half of the aerosol is cleared after approximately 15
minutes, with minimal activity remaining after 6 hours1718. A breath-actuated bidirectional
delivery device (OptiMist; OptiNose AS, Oslo, Norway) has been developed to address
the limitations of nasal pump spray. This device, generating drops of 43 m diameter,
demonstrates larger cumulative deposition in the region of the middle meatus and less
anterior segment deposition compared to a conventional nasal pump spray19.

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Nebulizers deliver medication in mist form, and are commonly used to delivery drugs to the
lower airway. A variety of nebulizers have been developed for targeted sinonasal drug
delivery (Table 2). SinuNeb (PARI Respiratory Equipment, Inc, Midlothian, VA) is a
passive-diffusion system; ViaNase (Kurve Technology Inc, Lynnwood, WA) is a vortexpropelled system12. PARI Sinus Pulsating Aerosol System (PARI GmbH, Starnberg,
Germany) is a pulsating nebulizer that has refined particle size distribution and flow rate20.
Studies on the pulsating aerosol system demonstrated improved posterior nasal cavity
deposition with access to the ostiomeatal complex and slower clearance times compared
with nasal pump sprays1718, 20. Although nebulizers represent a more technologically
evolved form of a traditional spray pump, the literature to support the efficacy of drug
delivery with nebulizers is still poor7, 10, 12, 21.
Patient positioning for drug delivery
There is no consensus on the most effective position for delivering topical drugs into the
nose and paranasal sinuses. Many commercial products recommend a head-down, over-thesink, or nose-toground position for nasal irrigation. This makes the residual runoff easy to
collect and is practical for patients. The delivery of nasal drops relative to head position has
been studied13, 22. One study found that the Mygind and Ragan (left lateral and supine)
positions were more effective than the Mecca and Head Back positions for delivery into
the middle meatus22. However, this has not been supported in other studies13, 2326. Headdown or vertex-to-floor position has been suggested to lead to better frontal distribution
post-ESS27. Positioning is more relevant for low-pressure delivery systems. For example,
when using the neti pot, the Mygind head position allows for the gravity-dependent

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drainage into the contralateral nasal wall and sinuses. Positioning with high-pressure
delivery systems may have less clinical importance5.

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Drugs and Compounds


Saline
Saline irrigations and sprays are the most commonly used intervention for rhinitis and
rhinosinusitis. Nasal saline has its roots in homeopathic medicine. Nasal washing is an
ancient Ayurvedic technique known as Jala neti, which means nasal cleansing in Sanskirt.
Today, it is often used as an adjunctive treatment for treatment of chronic rhinosinusitis. Its
use has been advocated both before and following sinus surgery, and in the latter case to
thoroughly cleanse the sinonasal passages and promote mucosal healing. Much of the
support for this intervention has been anecdotal, however recent literature provided evidence
to support the use of nasal saline for symptom improvement28.

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The physiological basis for the benefit of saline is unclear. The mechanical clearance of
mucus by saline is thought to be the most important factor. Both isotonic and hypertonic
saline appear to have a positive effect on mucociliary transport time2930. This is thought to
be due to improved rheologic properties of the sol layer rather than improved ciliary beat
frequency3132, although the data regarding ciliary beat frequency has been conflicting3233.
Other theories on the beneficial effects of saline include its nasal mucosal protective effect
and its ability to remove antigens, inflammatory mediators, and biofilm.
A Cochrane review reported that saline improves symptoms and disease specific quality of
life scores when compared to no treatment, either a single modality or as an adjunctive
treatment28. Although there is evidence that hypertonic solutions improve mucociliary
clearance30, 34, no difference was found in symptoms scores when comparing isotonic
(0.9%) to hypertonic saline28. Hypertonic preparations have been shown to elicit some pain
and discomfort at concentration above 2.7%35. At concentrations approaching 5.4%, patients
experience significant nasal obstruction due to vasodilation and there is reduced airspace as
determined by acoustic rhinometry35.

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The common delivery methods of topical saline include squeeze bottle, atomized spray, and
Neti pot. There have been few studies comparing the efficiency of saline on symptom scores
by means of delivery mechanism. Pynnonen et al. showed greater efficacy of saline
irrigation versus saline spray for providing short term relief of chronic nasal symptoms36.
This study focused on a community population of patients with sinonasal complaints and
excluded patients with recent sinus surgery. The efficacy of saline in non-operated verses
post-surgical must be inferred from the aforementioned anatomic studies28.
Saline is the cornerstone of treatment in the rhinologists armamentarium of topical therapy
for CRS, in part because it is very low risk with minimal adverse effects. The Cochrane
study showed no serious adverse event in over 1650 patients in published trials28. Most
patients tolerate nasal saline irrigation well, and even recommend this to family and friends
with sinus problems37. A small subset of patients will not tolerate nasal saline irrigation due
to discomfort or inconvenience. The most common minor complaints include nasal burning,
irritation, and nausea28. Delivery systems have developed around topical saline to improve
distribution and patient compliance. Since there are currently no approved drugs for the
treatment of CRS, saline delivery systems are often employed for off-label use of drugs as
topical agents.

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Corticosteroids

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Corticosteroids are potent medications that broadly target pro-inflammatory pathways.


While CRS is a heterogeneous disorder with a multifactorial etiology, mucosal inflammation
is a cardinal feature of the disease that contributes to the symptoms and histopatholology.
Both systemic and topical corticosteroids are used to treat chronic rhinosinusitis with and
without nasal polyposis (CRSsNP and CRSwNP, respectively). Topical corticosteroids are
favored over systemic corticosteroids because of the decreased potential for significant side
effects, especially with prolonged use.
Topical nasal steroids are effective for the treatment of CRSwNP, and are often considered a
first-line treatment option3839. Currently, only one intranasal steroid, mometasone furoate
is FDA-approved for the treatment of nasal polyps in CRS. However, various non-approved
topical steroids are commonly used in practice today. There is strong evidence for the
treatment of CRSwNP with intranasal steroids in terms of reducing polyp size on endoscopic
examination39. Topical mometasone, fluticasone, and budesonside have the best evidence
for use, especially in the post-ESS state39. On the other hand, the evidence for intranasal
steroids for CRSsNP is not well-established. A Cochrane review on CRSsNP found that
intranasal steroids improved symptoms overall, but the pooled studies were diverse in
outcome measures, delivery methods, and surgical status40. Similarly, a meta-analysis found
insufficient evidence that intranasal steroids demonstrated a clear benefit in CRSsNP41.

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An emerging trend for the treatment of refractory CRSwNP is the use of off label otic,
ophthalmic, or respiratory formulations of corticosteroids as topical agents delivered to the
nose4244. Budesonide irrigations have gained significant recent interest in the U.S. It is
often prescribed as a 0.5 mg in 2 mL respules diluted in 240 mL squeeze bottle irrigation to
be used twice daily. Initial studies have shown no evidence of adrenal suppression4446. In
the United Kingdom and some areas of Europe, solutions of either betamethasone or
fluticasone propionate are commercially available as nasal drops and used to treat
CRSwNP47.

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Nasal pump sprays, the most common delivery method of intranasal corticosteroids, have
almost no sinus penetration in non-operated patients6, 21. Snidvongs et al. found no
difference in terms of symptom scores or response to treatment between non-operated and
post-operative patients40. Other methods for delivery of corticosteroids into the sinonasal
cavity include aerosol, irrigation, and nasal drops. Some studies have reported delivery via
direct cannulation via an intranasal tube48 or intrasinus tube4950. The Cochrane review
showed no difference in outcomes based on delivery method40. Topical corticosteroids can
cause minor side effects of headaches, epistaxis, dryness or burning; significant adverse
events are extremely rare51.
Antibiotics
Oral antibiotics are effective in the treatment of chronic sinusitis and its acute
exacerbations5254. Topical antibiotics have thus emerged as adjunctive treatment for CRS
because they offer the potential for high local concentration at the desired target site with
minimization of systemic side effects. The literature supports both nebulized- and irrigationtype preparations of topical antibiotics. A systematic review found some evidence for
irrigated or nebulized antimicrobials, but no evidence for delivery by nasal sprays55.
Irrigation with topical antibiotics has been shown to be effective in CRS5556, and nebulized
antibiotics result in longer infection-free periods compared to standard oral and intravenous
antibiotics57.
Topical tobramycin is a common topical antibiotics used to treat CRS. Aerosolized forms of
this antibiotic were initially used in the treatment of pseudomonal pulmonary infections in
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cystic fibrosis (CF) patients. Studies of tobramycin nasal irrigations in CF suggest reduction
in the likelihood of repeat sinus surgery56 and improvement in outcome scores58. Mupirocin
is a topical antibiotic that is effective against Gram-positive bacteria, including Methicillinresistant Staphylococcus aureus (MRSA). It displays very high levels of activity against
Staphylococcus aureus even in nasal secretions59, and possibly has anti-biofilm activity in
vitro60. Muporicin is most often employed in patients with Staphylococcus aureus -related
CRS who have failed medical or surgical therapy6162. A growing concern is the
development of mupirocin resistance, and mupirocin-resistant strains of MRSA may make
the topical use of mupirocin obsolete in the future.
Antifungals

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A subset of patients with CRS has evidence of fungus in the sinonasal tract, although a
consistent role in disease pathophysiology is not well established. In allergic fungal sinusitis,
fungal elements are believed to underlie an IgE-mediated hypersensitivity that drives the
eosinophilic inflammatory process. Antifungals have been suggested as systemic or topical
preparations when fungus-related sinus inflammation is suspected. Since systemic
antifungals have significant side effects that involve the liver and kidney, topical antifungals
are more often advocated as a form of treatment for CRS63. There is conflicting literature on
the efficacy of topical antifungals. Ponikau et al. showed a benefit of intranasal amphotericin
B in double-blinded randomized control trial64. Others have not been able to replicate these
findings, and found no benefit of topical antifungals6568. A Cochrane study also found no
evidence to support the use of antifungals in CRS69, however there was significant
heterogeneity of the surgical state, delivery technique, and medication concentration in the
included studies. Amphotericin B dosage in the literature has ranged from 100 ug/ml to 300
ug/ml69. The Food and Drug Administration (FDA)-approved concentration is 100 ug/ml,
but Shirazi et al. showed that concentrations of at least 200 ug/ml are needed for fungicidal
activity in vitro70.
Other agents

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SurfactantSurfactants are compounds that lower the surface tension of liquids and are
thought to improve mucocilliary clearance by reducing the adherence of mucus to the
epithelial layer. Surfactants can also interfere with microbial cell membrane permeability
and disrupt cell membranes. Of recent interest, surfactants have been suggested to have a
preventive role against bacterial biofilm formation7172. There are many commercially
available surfactant products on the market. Treatment with Johnson & Johnson baby
shampoo (a combination of PEG-80 sorbital laurate, cocamidopropyl betaine, sodium
trideceth sulphate) at 1% concentration has demonstrated improved patient symptom scores
in the treatment refractory CRS72. Citric acid/zwitterionic surfactant (CAZS) has been
investigated in animal studies and has showed to be effective at reducing biofilms73. In
addition to its mucolytic and antibiofilm properties, a recent cadaver study showed that
when combined with surfactant, saline irrigations improved penetration into non-operated
sinus ostia74.
There is limited literature investigating the safety of topical surfactants. Chiu et al.
demonstrated that topical surfactant did not cause any significant damage to the cilia or
epithelial cells after a short exposure in murine nasal explants75. However, a rabbit study
using CAZS demonstrated a temporarily denudement of the respiratory cilia76. Clinically,
patients have complained of minor side effects of nasal and skin irritation, but there have
been no serious adverse side effects reported in the literature72. There have been anecdotal
reports of olfactory dysfunction associated with prolonged use of one commercial surfactant
product, leading to temporary withdrawal from the market and subsequent patient warnings.

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Further investigations are needed to examine the consequences from supraphysiologic


exposure to surfactant.

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Natural & Homeopathic Agents: Manuka honey and phytopharmaceuticals


Manuka honeys derived from the floral source in tea trees (Leptospermum spp) in New
Zealand has recently been described as a natural, inexpensive, and non-toxic topical therapy
for CRS77. The benefit of Manuka honey is suggested to derive from antimicrobial activity
against a broad spectrum of grampositive and gram-negative bacteria in their planktonic
states7879 and potentially against biofims80. Methylglyoxal (MGO), a derivative from the
manuka flower, is thought to be the main antimicrobial agent, with honey potentiating its
effects through an unknown mechanism81. In-vivo studies are needed to determine clinical
efficacy. Phytopharmaceuticals are compound medications composed of numerous herbal
products. Reports from Europe have reported the use of phytopharmaceuticals to treat
sinusitis8283. No clear evidence exists for these alternative therapies, and thus counseling
homeopathically-biased patients is important.

New and Future Directions

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Further refinement of intranasal drug delivery will demand increasingly sophisticated


delivery devices and techniques. Currently, topical drug delivery methods are optimized in
cadaveric models or by employing dyes and radioisotopes to study drug penetration in live
human subjects. Advances in computer modeling capability now allow detailed experiments
of sinonasal drug penetration to be performed in silico84. At this time, such computer-aided
models cannot accurately reflect physiologic factors inherent in CRS, however. In the
laboratory, human sinonasal epithelial cell cultures have been advanced as a model system
to study cellular and molecular mechanisms affecting topical drug delivery85. There is still
great potential in U.S. market for intranasal drug delivery given the shortcomings of current
products and the challenges with drug delivery devices. Together, the integration of
anatomic and physiologic models along with the growing market demand will pave the way
for future research and provide the best information on topical drug delivery to the sinonasal
cavities.

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Ideal characteristics for delivery devices include accurate and repeatable dosing, consistent
delivery to targeted site, patient-independent actuation, and effective compliance
monitoring86. Ideal characteristics for the medication include prolonged mucosal contact
time, high local absorption, and minimal depletion5. Newer drug delivery strategies, such as
drug-eluting stents, are addressing the shortcomings of existing nasal aerosol delivery
techniques. The promise of liposomal and nanoparticle technology may yield devices for
human trial for the treatment of CRS in the near future.
Drug-Eluting Stents
Stents allow for the slow release of topical drugs at targeted sites, and have been reported for
use in the paranasal sinuses since the early 2000s. In animal models, drug-eluting stents
have shown decreased granulation tissue without any epithelial damage, decreased postoperative osteoneogenesis and stromal proliferation, and negligible systemic
absorption8788. Most drug-eluting stents have focused on corticosteroids, but antimicrobialeluting stents have also been described8990. The Relieva Stratus Spacer (Acclarent, Menlo
Park, California), introduced in 2009, is a non-bioabsorbable stent designed for the ethmoid
cavity. The device is approved for saline, however, in an attempt to deliver corticosteroid,
physicians have placed triamcinolone into the device reservoir. Investigations have revealed
that the device eludes 0.3 ml of triamcinolone acetate 40 mg/ml over 2 to 4 weeks91.
Approved by the FDA in 2011, the Propel sinus implant (Intersect ENT, Palo Alto,
California) is a newer bioabsorbable implant that self-expands in the sinus cavity and
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releases 370 g of mometasone furotate over 4 weeks92. Prospective double-blinded trials


on a bioabsorbable drug-eluting stent used after ESS in patients with CRS have shown
significantly reduced inflammation and prevention of significant adhesion compared to a
control stent92. One critique of the current stents on the market is that the total dosage of
corticosteroid is low, and may not be sufficient to combat the degree of inflammation,
especially in cases of recalcitrant CRS. Designing stents with larger-dosage steroid or
longer-duration of drug elution may improve the efficacy of these devices. Drug-eluting
stents are a promising new technology in the treatment armamentarium for CRS.
Nanoparticles, Microspheres and Liposomes

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Nanoparticles are solid colloidal drug carriers ranging from 10 to 1000 nm in diameter and
composed of synthetic, natural, or semi-synthetic polymers encapsulating the drug molecule;
mircospheres are larger versions of these drug-encapsulating polymers that range from 1 to
1000 m in diameter with most under 200 m93. The major nanoparticle material that has
been studied for nasal drug delivery is chitosan. Chiotsan is a biocompatible cationic
polysaccharide consisting of N-acetylclucosamine and D-glucosamine units that is produced
by the deacetylation of chitin, the main component of crustacean exoskeleton9495. As a
drug carrier, chitosan nanoparticles inhibit enzymatic metabolism and thus allow for slow
and sustained drug release96. Nanoparticles conjugated with vaccines have been developed
for nasal vaccination, and the nasal delivery of insulin, heparin, and other proteins via
chitosan nanoparticles has been described9394, 96. Liposomes are phospholipid vesicles are
composed by lipid bilayers enclosing aqueous compartments that have the advantage of
encapsulating molecules of various sizes and solubility profiles to increased membrane
penetration99. Intranasal applications of liposome have also been reported9799. Although its
application for the treatment of CRS has yet to be studied, nanoparticle- and liposome-based
delivery devices may represent a future trend for the delivery anti-inflammatory and antimicrobial agents to the paranasal sinuses.

Conclusion

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The increasingly central role of topical therapies in the medical management of CRS has
been associated with a burst of related research, technology, and commercial products. This
interest in topical agents has arisen from decades of experience with endoscopic sinus
surgery and a growing recognition of underlying persistent inflammatory processes in
surgically recalcitrant CRS. The surgical goals of enlargement of sinus ostia and outflow
tracts have thus shifted from a direct reversal of inflammation to a secondary role in
improving access for subsequent topical treatments. A summary of the evidence for topical
therapies is shown in Table 3. While more evidence is needed to prove the validity of this
approach, the critical importance of creating access surgically has been firmly established
for sinus delivery using current devices. Pump sprays and nebulizers have very limited sinus
penetration in the unoperated state, although it is possible that new procedures and delivery
systems will be developed that will not require wide openings into the sinuses. Nasal saline
and intranasal corticosteroids continue to be the most studied and commonly employed
agents for long-term topical management of CRS. Further research is needed to establish the
efficacy of topical antimicrobials and surfactants, and existing delivery systems for these
and other agents continue to evolve.

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Table 1

Delivery Techniques

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Positive/High Pressure

Negative/Low Pressure

High Volume

Squeeze bottle
Bulb syringe
Pressurized sprays
Pulsatile jet

Neti pot
Nasal inhalation

Low Volume

Pump sprays

Drops

Atomization

Catheter instillation
Nebulizer

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Table 2

Nebulizer Systems

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Particle Size

Direction

Velocity

Passive-Diffusion Nebulizers (SinuNeb)

Smaller particles (3 m)

Constant direction

Slower velocity

Vortex-Propelled Nebulizers (ViaNase)

Larger particles (911 m)

Multiple directions

Faster velocity

Pulsating Aerosol Delivery Device (PARI Sinus)

Smaller particles (3 m)

Aerosol stream superimposed


by a pulsation

Very slow velocity (36 L/


minute)

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Table 3

Summary of Evidence for Topical Delivery

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Study

Study Characteristics

Conclusions

Saline

Harvey et al, 2007

Cochrane review; Included 8 RCTs

Saline irrigation is well tolerated; No


significant adverse effects; Beneficial effect
for treatment of CRS

Corticosteroids

Joe et al, 2008

CRSwNP Systematic review & Meta-analysis;


Included 13 studies; 6 of these used for metaanalysis

Topical steroids decreased polyp size in


CRSwNP

Snidvongs et al, 2011

CRSsNP Cochrane review; Included 10 RCTs

Topical steroids is beneficial for CRSsNP in


symptom control; Adverse effects are minor

Anti-Bacterials

Lim et al, 2008

Systematic review; Included 10 studies (2 RCTs, 2


controlled studies, 5 cohorts, 1 expert report)

Not first-line therapy; Stronger evidence


(level IIb) for cystic fibrosis patient; Can
use in refractory cases

Anti-Fungals

Lim et al, 2008

Systematic review; Included 4 studies (3 RCTs, 1


cohort)

No evidence for antifungals in CRS

Harvey et al, 2011

Cochrane review; Included 6 RCTs

No evidence for antifungal in CRS

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